Immunosuppressive effects of pteridine derivatives

Abstract

This invention relates to a group of trisubstituted and tetrasubstituted pteridine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, dihydro- and tetrahydro-derivatives and enantiomers, possessing unexpectedly desirable pharmaceutical properties, in particular which are highly active immunosuppressive agents, and as such are useful in the treatment in transplant rejection and/or in the treatment of certain inflammatory diseases. These compounds are also useful in preventing or treating cardiovascular disorders, allergic conditions, disorders of the central nervous system and cell proliferative disorders.

1. A pteridine derivative selected from the group consisting of:
 2-amino-4-morpholino-6-(4-acetanilide)pteridine, 
 2-amino-4-morpholino-6-(3-acetanilide)pteridine, 
 2-amino-4-morpholino-6-(4-aminophenyl)pteridine, 
 2-amino-4-morpholino-6-(3-aminophenyl)pteridine, 
 2-amino-4-morpholino-6-(4-benzoylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(4-phenoxyacetylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(4-propionylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(4-furoylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(4-cyclohexanoylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-[4-(4-chlorobenzoyl)aminophenyl]pteridine, 
 2-amino-4-morpholino-6-(4-benzyloxyacetylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(4-isonicotinoylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(4-naphtoylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(4-methylsulfonylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(4-ethylsuccinylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-[4-(4-methylbenzoate)aminophenyl)pteridine; 
 2-amino-4-morpholino-6-(3-benzoylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(3-benzensulfonylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(3-phenoxyacetylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(3-isonicotinoylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(3-cyclohexanoylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-[3-(4-methylbenzoate)aminophenyl]pteridine; 
 2-amino-4-morpholino-6-(3-ethylsuccinylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(3-ethylmalonylaminophenyl)pteridine; 
 2-amino-4-morpholino-6-(3-benzyloxyacetylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-(3-ethylsulfonylaminophenyl)pteridine, 
 2-amino-4-morpholino-6-[3-Boc-(L)-phenylalanine-aminophenyl]pteridine; 
 2-amino-4-morpholino-6-[3-Boc-(D)-phenylalanine-aminophenyl]pteridine; 
 2-amino-4-morpholino-6-[3-Boc-(L)-tryptophane-aminophenyl]pteridine; 
 2-amino-4-morpholino-6-[3-Boc-(D)-tryptophane-aminophenyl]pteridine, 
 2-amino-4-morpholino-6-(4-hydroxyphenyl)pteridine, 
 2,4-di-(thienyl-2-methylarnino)-6-(3,4-dimethoxy-phenyl)pteridine, 
 2-amino-4-morpholino-6-(4-benzyloxyphenyl)pteridine, 
 2-amino-4-morpholino-6-(4-(phenethyloxy)-phenyl)pteridine, 
 2-amino-4-morpholino-6-(4-phenoxy-butyronitrile)pteridine, 
 2-amino-4-morpholino-6-(4-propoxy-phenyl)pteridine, 
 2-amino-4-morpholino-6-(4-phenoxy-butyric acid ethyl ester)pteridine, 
 2-amino-4-morpholino-6-(4-phenoxy-acetic acid ethyl ester)pteridine, 
 2-amino-4-morpholino-6-(4-(2-methoxyethoxy)-phenyl)pteridine, 
 2-amino-4-morpholino-6-(4-butoxy-phenyl)-pteridine, 
 2-amino-4-(diethanolamino)-6-[[3,4-(dimethoxyphenyl)]pteridine, 
 2-amino-4-(benzylamino)-6-[[3,4-(dimethoxyphenyl)]pteridine; 
 2-amino-4-(phenylethylamino)-6-[[3,4-(dimethoxyphenyl)]pteridine, 
 2-amino-4-(2-thienylmethylamino)-6-[[3,4-(dimethoxyphenyl)]pteridine, 
 2-amino-4-thiomorpholine-6-[[3,4-(dimethoxyphenyl)]pteridine. 
 
     
     
       2. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to  claim 1 . 
     
     
       3. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to  claim 1 , and further comprising one or more biologically active drugs selected from the group consisting of immuno-suppressant and/or immunomodulator drugs. 
     
     
       4. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to  claim 1 , and further comprising one or more immunosuppressant drugs selected from the group consisting of cyclosporin A; pentoxyfylline; daltroban, sirolimus, tacrolimus; rapamycin; leflunomide; mycophenolic acid and salts thereof; azathioprine, brequinar; gusperimus; 6-mercaptopurine; mizoribine; chloroquine; hydroxy-chloroquine; etanercept; infliximab; and kineret. 
     
     
       5. A pharmaceutical composition comprising as an active principle at least onepteridine derivative according to  claim 1  and further comprising one or more immunomodulator drugs selected from the group consisting of acemannan, amiprilose, bucillamine, ditiocarb sodium, imiquimod, Inosine Pranobex, interferon-β, interferon-γ, lentinan, levamisole, pidotimod, romurtide, platonin, procodazole, propagermanium, thymomodulin, thymopentin and ubenimex. 
     
     
       6. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to  claim 1  and further comprising one or more pharmaceutically acceptable carriers or excipients.